Living organisms survive as an individual by adjusting and maintaining their physical and chemical states to and within certain stable physiological conditions corresponding to changes in internal and external circumstances. To maintain and adjust such homeostasis, the living organism always produces various substances in vivo. Upon invasion by viruses, bacteria, etc. and upon generation of tumor cells, the organism also produces certain substances in vivo which are resistant to such external and internal invasions. However, if the biofunctions are unbalanced for some reason and it becomes chronic, so-called morbidity results causing various diseases.
The ideal way of curing the disease is to activate and adjust the function of the organism to maintain homeostasis so that the abnormal imbalance of the disordered biofunction is restored to a normal state. It has been well known that the maintenance and the normalization of the biofunction are especially carried out by various receptors on cell surfaces and the ion channels such as sodium, potassium, calcium, etc.
It has been known that, upon growing older, the ability of DNA to recover against damage decreases in mammalian cells. It is also known that the production of free radicals in vivo promotes aging, collagen disease and generation of cancer. For example, collagen is a noncellular substance widely present in skin, blood vessels, cartilage, eye balls, kidneys, etc. Crosslinking of collagenous materials proceeds with advancing age whereby their elasticity decreases and they become hard. It has been well known that, in patients suffering from diabetes, an excessive crosslinking of the collagenons materials proceeds as a result of a continuing high sugar level in the blood. The crosslinking of the collagenous material may result in cataracts, atherosclerosis, renal diseases, peripheral nervous disorders, etc.
The present inventors have focused on the function of maintaining homeostasis of living organisms which adjusts to and recovers from strains in the nervous, immunological and endocrine systems. The strains are caused by a disorder of cell functions in vivo as a result of diseases and aging. The present inventors have conducted an extensive investigation to ascertain the substances which: 1) are produced at the resisting stage of organisms against internal and external stresses (i.e., at the activating stage of the living tissues), and 2) promote the natural curing ability of the organisms to participate in the normalization of the biofunctions.
A known mechanism for adjusting the complicated functions in vivo is an enzymatic system called the kallikrein-kinin system. With respect to this plasma kallikrein-kinin system, it is believed that a blood coagulation factor XII (a Hageman factor, abbreviated as FXII) is activated due to stimulation by a lesion or by an invasion to the tissues in vivo whereby a series of enzymatic reactions is induced. Thus, the activated blood coagulation factor XII (abbreviated as FXIIa) acts on the plasma prekallikrein which exists in the same plasma to convert it to a plasma kallikrein which is an enzyme in an activated form. Then, the plasma kallikrein acts on a high-molecular-weight kininogen (abbreviated as an HK) in the plasma to liberate bradykinin.
The bradykinin which is a product of the plasma kallikrein-kinin system exhibits various physiological activities such its dilation of peripheral blood vessels which lowers blood pressure, acceleration of permeation of blood vessels, contraction or relaxation of smooth muscle, induction of pain, generation of inflammation, migration of leucocytes, liberation of catecholamine from the adrenal cortex, etc. Bradykinin has also been known as a mediator for induction of pain, inflammation and allergic reactions. Accordingly, when an excessive liberation and production of bradykinin is inhibited, it is possible to relieve pain, inflammation, allergic syndromes, etc. and to make such unhealthy states normal.
As mentioned above, bradykinin is liberated or produced in the reaction of plasma kallikrein with the high-molecular-weight kininogen HK. Accordingly, substances which inhibit kallikrein production in the plasma kallikrein-kinin system and prevent excessive production of bradykinin may be useful as pharmaceuticals such as analgesics, antiinflammatory agents, antiallergic drugs, etc.
In the present invention physiologically active substances which possess biofunction-adjusting and maintenance properties are obtained by subjecting tissues to stress or activation and then recovering the active substances produced as a result of the induced stress or activation. The physiologically active substances of the present invention provide recovery from and normalizes abnormal functions of the diseased state. They inhibit production of plasma kallikrein. They improve peripheral blood flow and are useful as analgesics, antiinflammatory agents, antiallergic agents, and other pharmaceuticals.